DXA, bone markers, definition of ‘success’ Dr John Lindsay

1. Is my treatment working doctor?
DXA, bone markers, definition of ‘success’
Dr John Lindsay
NOS Meeting
Galgorm Resort & Spa
5th October 2017

2. Objectives
• To consider utility of current anti-osteoporosis
therapies
• Review the use of DXA monitoring during
treatment
• Explore role of bone turnover markers,
interpretation and recent guidelines
• Consider ‘definition of success’

3. Osteoporosis Medications
Anti-resorptive
Alter quality
Anabolic
Extra-skeletal
e.g. reduce falls
• Goals of currently available
medications:
• Reduce the risk of fracture
• Improve bone strength
- Increase bone mass
- Possibly improve bone
architecture

4. Spine
BoneTurnover
BoneMineralDensity
Femur
BF
FractureRate
PreMP Range
BR
Time
Rapid decrease in bone
resorption (BR), followed by a
decrease in bone formation (BF)
Time
Refill remodeling space +
secondary mineralization 
 Increase in BMD spine >
hip
Reduction in
fracture risk
Bisphosphonates
Reduce BTMs, Increase BMD and Reduce Fracture Risk

5. Bisphosphonates Reduce Vertebral Fracture Risk
Data from pivotal trials
ZOL 5 mg
Risedronate
Alendronate
Ibandronate
Years Years Years Years
0‐1 0‐2 0‐3 0‐1 0‐2 0‐3 0‐1 0‐2 0‐3 0‐1 0‐2 0‐3
RelativeRiskReduction(%)
71%
0
10
20
30
40
50
60
70
60%
70%
65%
55%
41%
62%
48%
58%
61%
52%
65%

6. Teriparatide Increases BMD
RCT of 1637 women with postmenopausal osteoporosis
and 1 vertebral fractures treated an average of 18
months with placebo, 20 µg PTH (1-34)
NS
NS
P<0.001
P<0.001

7. 0 6 12 2418 30 36
The effect of denosumab on time to first hip fracture through 36
months in the overall FREEDOM population1,2
ARR = absolute risk reduction; RRR = relative risk reduction
1. Adapted from Cummings SR, et al. N Engl J Med. 2009;361:756-765..
2. Prolia® (denosumab), Summary of Product Characteristics last accessed February 2013
Placebo, n 3,906 3,799 3,672 3,538 3,430 3,311 3,221
Denosumab, n 3,902 3,796 3,676 3,566 3,477 3,397 3,311
Number of patients at risk
CumulativeIncidence(%)
Month
0.0
0.4
0.8
1.2
0.7%
1.2%
Placebo
Denosumab 60 mg Q6M
RRR = 40%
ARR = 0.5 %2
p = 0.04

8. Long-term Denosumab
Bone et al. Lancet Diabetes Endocrinol 2017; 5: 513–23

9. Monitoring Osteoporosis Therapy
• Goal of treatment= reduce fragility fracture occurrence
• Fragility fracture incidence is low; absence of fracture during therapy
does not necessarily mean treatment is effective
• However, fracture occurrence on therapy does not necessarily indicate
treatmentfailure
• Surrogates such as BMD and biochemical markers to monitor treatment
can be useful
• Changes in an ideal surrogate marker during therapy should reflect
changesin fracture risk

10. NNT to prevent a secondary vertebral
and non-vertebral fracture
Saito Osteoporos Int 2017.
DOI 10.1007/s00198-017-4175-0
Medication Secondary vertebral fracture
(ACR = 2.88%)
Secondary non-vertebral
fracture (ACR = 8.65%)
NNT (95% CI) NNT (95% CI)
Bisphosphonate 74 (66, 85) 28 (23, 43)
Etidronate 71 (54, 119) Effectiveness not established
Alendronate 77 (64, 96) 24 (18, 53)
Risedronate 89 (85, 92) 21 (16, 55)
Pamidronate 62 (46, 159) Effectiveness not established
SERMs 89 (81, 99) Effectiveness not established
PTH 56 (47, 76) 32 (21, 116)
Calcitonin 152 (87, 3333) N/A
NNT to prevent a secondary vertebral and non-vertebral fracture
NNT number needed to treat, ACR assumed control
risk, CI confidence interval, SERMs selective estrogen receptor
modulators, PTH parathyroid hormone, N/A not available

11. Long-term Bisphosphonates
Adler et al. JBMR 2016; 31: 16–35

12. Reasons to Measure Serial BMD
• Untreated patients
◦ Significant loss may be an indication for treatment
and is associated with an increased fracture risk1
• Treated patients
◦ To monitor the response to therapy
- Increase or stable bone density is associated with
fracture risk reduction
- A loss of BMD is cause for concern
• Consider further evaluation (adherence, secondary
causes) for those who are losing BMD2
1Nguyen TV et al JBMR 2005;20(7):1195-1201
2Lewiecki EM J Clin Densitom. 2003;6(4):307-14

13. Fracture Risk Doubles with every SD
decrease in BMD
0
5
10
15
20
25
30
35
-5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0
Bone Density (T-score)
Relative
Risk for
Fracture

14. Approach to Monitoring
• Compare “apples withapples”
• Critically assess the DXA images on the two comparison studies
• The region of interest (ROI) must be the same
• The measuredarea should be comparable
• Compare the BMD, not the T-score
• How much of a difference is real?
• If there is a difference, what does it mean?
• If the ROI appears the same but the area is different, look for improper
positioning,incorrect scan analysis, and/or artifacts (fractures, degenerative
changes,etc.)

15. L1-L4 BMD 0.896 g/cm2
T-score = -2.4
L1-L4 BMD 0.853 g/cm2
T-score = -2.7
Loss = 0.043 g/cm2 (4.8%), exceeds least significantchange
65 year old, initial spine T-score = -2.4, treated with a bisphosphonatefor 1 year
Repeat DXA reports bone loss
Baseline Follow-up
The Importance of Comparing
“Apples With Apples”

16. Comparing “Apples With Apples”
Importanceof Hip Positioningon Femoral Neck BMD
Baseline
1.009 g/cm2
Follow up (initial)
1.017 g/cm2
+0.008 g/cm2
Follow up (repositioned)
0.966 g/cm2
−0.043 g/cm2

17. Least Significant Change (LSC)
• Precision error at your centre
• Desired confidence level(95%)
• Perform precision study on patients representative of
your typical patientpopulation
◦ This will help prevent over-calling of significant change
LSC = (precision error) × 2.77
to have 95% confidence that the change isreal

18. Serial BMD
Baseline spine BMD
Repeat spine BMD
Difference
0.866 g/cm2
0.832 g/cm2
0.034 g/cm2
LSC 0.028 g/cm2
Exceeds or Equals LSC Yes
• Change is significant
• Note that % change is:
−(0.034/0.866) × 100= loss of 4% ± LSC
= 4% ± 2.8%

19. Selection of Skeletal Site and Region of
Interest for Monitoring Changes
• PA spine preferred
◦ Best precision
◦ Most responsive to therapy
◦ Use L1-L4 value if possible
• If PAspine cannot be used
◦ Total hip preferred (better precision)
◦ Femoral neck (poor precision)

20. If There Is a Difference in BMD at
Follow-up, What Does it Mean?
• What is a satisfactory response to treatment?
◦ Significant gain in BMD?
◦ Stable BMD?
• What is cause for concern?
◦ Failure to gain?
◦ Significant loss?

21. Cummings, et al. JAMA 1998:280:2077-2082
Fracture reduction is greater than
would be predicted by BMD increase

22. Monitoring Therapy With BMD
• If there is loss of BMD that exceeds LSC (95%
confidence)
– Check compliance with medication
– Assure proper administration
– Check calcium and vitamin D intake
– Look for underlying disease or condition
• What about bone turnover markers for monitoring response
to treatment-is there a role?

24. Bone Turnover Markers Change Sooner
than BMD but Have More Variability
• Bone Mineral Density:
◦ BMD changes slowly (= static measurementof
skeletal status)
◦ Low within-person variability
◦ Measurement = precise
◦ Small changes in response to antiresorptive therapy
• Markers
◦ Dynamic measure of skeletalstatus
◦ Larger changes in responseto therapy (within
months)
◦ ± great variability
1-2 yrs
D
0
3-6 months
Delmas P.Osteoporos Int 2000;11(Suppl.6):66-76.
D
LSC0

25. Bone Turnover Markers
Markers of bone resorption
◦ C-telopeptide (CTx)*
◦ N-telopeptide (NTx)
- Degradation products of type 1
collagen
Markers of bone formation
◦ Procollagen type 1 N- terminal
propeptide (P1NP)*
◦ Bone specific alkaline
phosphatase (BSAP)
◦ Osteocalcin
◦ C-terminals propeptide of type 1
procollagen
*recommended by
IOF and IFCC
Mellanby Centre, Sheffield, Bone Turnover Markers Course

26. Early Changes in Bone Turnover Markers are
Associated with Long-term Changes in BMD
RCT, postmenopausal women >65 yrs (n=373)
ALN, HRT, ALN+HRT vs. PBO for 3 years
Decrease in NTX at 6 months (%) Decrease in Bone ALP at 6 months (%)
8 8
6 6
4 4
2 2
0 0
<46 46-66 ->66
10 10
12 12
<46 46-66 ->66
Total Hip
PASpine
%changeinBMD
%changeinBMD
Adapted from Greenspan et al., J Clin Endocrinol Metab 2005, 90: 2762-2767
Total Hip
PASpine

27. Greater BSAP Reduction With Alendronate
at 1 Year is Associated with Greater Fracture
Risk Reduction at Years 2.5 - 4.5
PatientsWithFracture(%)
7.3
1.0
9.8
0.8
8.7
4.3*
3.8*
6.8*
0.2*
0
2
4
6
8
10
Spine Hip Non-Spine
Placebo (n=3,066)
Alendronate (<30% reduction BSAP)
Alendronate (> 30% reduction BSAP)
*p < 0.01 vs placebo
Adapted from Bauer DC, et al. J Bone Miner Res. 2004;19:1250-1258.

28. Bone Turnover Markers and BMD Response
Medication BTMs Spine Hip
Oestrogen  
Bazedoxifene/CEE  ()
Alendronate  
Risedronate  
Ibandronate  
Zoledronic acid  
Calcitonin ~ ~
Raloxifene  ()
Denosumab  
Teriparatide   

29. Variation in BTMs
Eastell R, Szulc P. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30184-5.

30. Conditions that affect BTMs
Eastell R, Szulc P. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30184-5.
Recent Fracture

31. Impact of drugs
Eastell R, Szulc P. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30184-5.

33. TRIO Study
Naylor et al. Osteoporosis Int. 2016 Jan;27(1):21-31.
By 12 weeks more than 80% of patients had decreased >LSC for CTX-I (56%) and PINP (38%)

34. Assessment of concordance
Diez-Perez A. Osteoporosis Int 2017

35. Alternative approaches
• Decrease BTMs below the mean of healthy pre-
menopausal women. Thresholds of:
– 35 μg/L for PINP
– 312 ng/L for serum CTX-I
• Close to the average values obtained in several
studies; may vary according to the assay used
Eastell R, Szulc P. Lancet Diabetes Endo 2017

36. Early Changes in Bone Markers Predict BMD
Response to Parathyroid HormoneTherapy
P1NP
Bauer et al., J Clin Endocrinol Metab 2006, 91: 1370

37. Options for clinical practice
• Monitoring individual response to treatment
– Further research required
• Absence of a change may indicate
– Poor concordance
– Inappropriate injection of Teriparatide
– Secondary osteoporosis
– Real absence of response to treatment
• ??monitor offset of treatment or negative impact on bone in
drug development
Eastell R, Szulc P. Lancet Diabetes Endocrinol. 2017; S2213-8587(17)30184-5.

38. Mellanby Centre, Sheffield, Bone Turnover Markers Course

39. Concordance
Never Sometimes Mostly Always
DXA BMD
Falling >LSC Stable within LSC Rising >LSC
BTMs
No response Resorption/formation response
Fracture
Multiple Single None
Is my treatment plan working doctor?
SUCCESS?

40. Summary & Conclusions
• Explored utility of current anti-osteoporosis
therapies
• Reviewed the use of DXA monitoring during
treatment
• Explored role of bone turn over markers,
interpretation and recent guidelines
• Considered factors around ‘definition of success’